Showing 4 ideas for tag "duchenne"

Goal 2: Reduce Human Disease

Triggers of pulmonary dysfunction in Duchenne

Pulmonary function generally remains stable in Duchenne until loss of ambulation. What is the trigger that occurs at loss of ambulation that initiates the cascade of pulmonary dysfunction?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

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: recommendations guiding care indicate that pulmonary function remains normal, requiring little or no monitoring prior to loss of ambulation. This finding has remained consistent both prior to, and with the advent of, corticosteroid therapy. It has been difficult to identify what triggers the cascade toward pulmonary dysfunction that, presumably, begins with nocturnal hypoventilation.

Feasibility and challenges of addressing this CQ or CC

gathering natural history data and the identification of biomarkers consistent with the onset and severity of pulmonary dysfunction in Duchenne, would allow an accurate delineation of pulmonary function and identify the need for respiratory assistance. A challenge to address is that there is controversy around which measures of pulmonary function most accurately identify the degree of pulmonary dysfunction present and respiratory assistance required. Discussions are needed around which guidelines for obtaining and evaluating spirometery are most appropriate and beneficial for this population. Given the sophistication of ongoing efforts in the natural history of Duchenne, by making the commitment of resources to longitudinal evaluation of pulmonary status, in parallel with other measures, it should be feasible to address this question

Name of idea submitter and other team members who worked on this idea Parent Project Muscular Dystrophy

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Goal 2: Reduce Human Disease

Mechanism of Cardiopulmonary dysfunction in Duchenne

What is the exact mechanism affecting the cardiopulmonary cascade of events that occurs in Duchenne?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

Very little is truly known about the cardiopulmonary cascade in Duchenne. While patients are tested (pulmonary function testing, sleep studies) and encouraged to use assistive devices (cough assist, non –invasive and invasive assisted ventilation), we have no insight into exactly what is happening to the diaphragm, accessory muscles, effects on the heart, etc. that results in sudden death. The investigation of this area is vital to the well being of this patient population, and represents a gap in both research and care.

Feasibility and challenges of addressing this CQ or CC

identifying the exact mechanisms of the cardiopulmonary decline in Duchenne would allow the development and implementation of appropriate interventions, delaying, and possibly, preventing this cascade of events that lead to sudden death in this disease. The implications for Duchenne are tremendous. Likewise, the implications for other muscular dystrophies resulting in cardiopulmonary deaths, as well as other diagnoses resulting in cardiomyopathy, cardiac and pulmonary failure, would benefit as well.

Name of idea submitter and other team members who worked on this idea Parent Project Muscular Dystrophy

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Goal 2: Reduce Human Disease

Correlation of genetic modifiers and cardiopulmonary fibrosis/dysfunction in Duchenne

What are the protective genetic modifiers that may be associated with a Duchenne phenotype more resistant to the development of cardiac and pulmonary fibrosis and subsequent pulmonary/cardiac dysfunction? . Are there genetic modifiers that may ameliorate or enhance the onset of cardiac and/or pulmonary dysfunction?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

The two major causes of death in Duchenne are cardiac and pulmonary dysfunction. The onset of cardiac and pulmonary dysfunction in people living with Duchenne follows a heterogeneous path, not necessarily consistent with the underlying genotype or onset musculoskeletal dysfunction. This can often be seen in siblings/relatives with identical genetic mutations and very different disease progression.

Feasibility and challenges of addressing this CQ or CC

A number of studies have provided some degree of evidence for the presence of genetic modifiers in Duchenne, which may affect disease onset and musculoskeletal progression. Two of these modifiers, LTBP4 and SPP1 have been shown to have a profound effect on time to loss of ambulation, establishing the need for and feasibility of identification of genetic variants that impact the cardiorespiratory phenotype in Duchenne.
Several reports have alluded to the impact of genetic modifiers on pulmonary and/or cardiac disease progression in animal models. Further studies validating the presence and impact of these modifiers may have implications for the prevention, or postponement, of cardiac and pulmonary dysfunction in Duchenne, as well as other, muscular dystrophies, allowing enhancement of both quantity and quality of life.
In addition, drug development with pulmonary and/or cardiac primary or secondary outcomes, may be impacted by populations with genetic mutations that include genetic modifiers. At least one of the already identified genetic variants affects skeletal muscle responsiveness to corticosteroid treatment. The validation of the presence, and impact, of these modifiers, may impact the outcomes of these trials, and help delineate populations most likely to benefit from these new therapies.

Name of idea submitter and other team members who worked on this idea Parent Project Muscular Dystrophy

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Goal 2: Reduce Human Disease

Correlation between abdominal/diaphragmatic fibrosis and cardiopulmonary dysfunction in Duchenne

Is there a correlation between the development of abdominal/diaphragmatic fibrosis and the development of cardio-pulmonary dysfunction? Are there mechanisms (i.e., pulmonary excursion therapy) that may prevent/postpone the development of diaphragmatic fibrosis and subsequent pulmonary dysfunction?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

currently there is no adequate method of evaluating the development of fibrosis in the diaphragm. Mdx mouse models have provided insight into this progression, and to a possible correlation between abdominal fibrosis and cardiac dysfunction.

Feasibility and challenges of addressing this CQ or CC

: Maintaining cardiopulmonary function in Duchenne has been the mainstay of therapy, however little attention has been given to the accessory muscles of respiration. Supporting the muscles of respiration may prevent or postpone the ongoing process or cardiopulmonary dysfunction, resulting in an increased the lifespan, and quality of life, of people living with Duchenne. The current base of researchers addressing the cardiopulmonary issues in Duchenne, as well as the resources to identify and track patients with cardiopulmonary dysfunction, enhances the feasibility of answering this question.

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